The University of Alabama at Birmingham (UAB) has an outstanding record in basic immunology and in testing of novel, translational therapies for autoimmune diseases. The UAB Autoimmunity Center of Excellence (ACE) is a multidisciplinary, collaborative program to unite these strengths to accelerate the development and testing of translational therapies for autoimmune disease. To accomplish this, the UAB ACE will promote basic and translational research and sponsor clinical trials of novel immunomodulatory agents. As part of this mission, the UAB ACE will foster communication between basic and clinical investigators and between those focused on different immune-mediated diseases at UAB and nationally. Four projects are proposed. The Clinical Component (Project 1) includes highly experienced investigators from six clinical areas. Two potential clinical trials are proposed, targeting Death Receptor 5 in Lupus, an approach developed at UAB, and IL-1 in psoriatic arthritis, using a high affinity blocker brought to UAB investigators by the pharmaceutical industry. Three basic projects center on the unifying theme of analysis of the interaction of T cells and cytokines and/or TNF-family factors in maintenance or restoration of tolerance, including: Project 2) function of Death Receptor 5 on activated T cells in autoimmunity, Project 3) the role of cytokines and TNF-family proteins in reconstitution of T cell tolerance after immunosuppression, and Project 4) the function of IL10-expressing T cells in tolerance in mucosal immunity. The interactive nature of these projects is illustrated by the fact that each basic project involves assays or models derived from at least one of the others. The Administrative Core will coordinate ACE activities, facilitate interactions and collaborations, promote scientific development, set the strategic agenda, and perform continuous evaluation of ongoing projects. The Immunomodulatory Studies Core will promote analysis of changes in cells or cytokines in human tissues in disease and in mechanistic studies of participants receiving biologic therapies. Both cores will serve all proposed projects. Thus, the ACE will unite UAB investigators to bring the strength of immunological research and the breath of experience in clinical trials in a range of immune-mediated diseases to jointly develop new therapies for autoimmunity.